Virtually all of the many antineoplastic drugs that are currently used in the treatment of cancer have very serious and harmful side effects. This is because cancer is generally treated with medications that interfere with the growth of rapidly dividing cells. Such medications can inhibit the growth of the cancer cells, but they almost always also inhibit the growth of normal cells that divide rapidly in the body. Some of the normal tissues that divide very rapidly include bone marrow (which produces blood cells), hair follicles, and intestinal epithelium. The usefulness of virtually all antineoplastic drugs is severely limited by the damage they cause to these normal tissues.
This invention relates to methods for treating neoplasia using both an antineoplastic vinca alkaloid derivative (a common chemotherapeutic) and a cyclic GMP (cGMP)-specific phosphodiesterase (PDE) inhibitor to reduce the side effects or increase the efficacy of vinca alkaloid derivative treatment.
The early vinca alkaloids, vinblastine and vincristine, were originally found in the Madagascar periwinkle. Later, vindesine and vinorelbine, semisynthetic derivatives of vinblastine were developed. The natural and semisynthetic all collectively referred to herein as xe2x80x9cvinca alkaloidsxe2x80x9d or xe2x80x9canti-neoplastic vinca alkaloids.xe2x80x9d
Vinca alkaloids act by inhibiting mitosis in metaphase. These alkaloids bind to tubulin, thus preventing the cell from making the spindles it needs to be able to move its chromosomes around as it divides. These alkaloids also seem to interfere with cells"" ability to synthesize DNA and RNA. They are all administered intravenously in their sulfate form once a week; these solutions are fatal if they are administered incorrectly, and can cause considerable tissue irritation if they leak out of the vein.
Vinblastine (xe2x80x9cVelban(trademark)xe2x80x9d) is typically administered at a dose of 6 milligrams per square meter of body surface. Vinblastine is mainly useful for treating Hodgkin""s disease, lymphocytic lymphoma, histiocytic lymphoma, advanced testicular cancer, advanced breast cancer, Kaposi""s sarcoma, and Letterer-Siwe disease. It has drawbacks, however. For example, patients with bacterial infections should not be given this drug, nor should pregnant women, since it caused severe birth defects in animal studies. In addition, common side effects include hair loss, nausea, lowered blood cell counts, headache, stomach pain, numbness, constipation and mouth sores. Bone marrow damage is the typical dose-limiting factor.
Vincristine (xe2x80x9cOncovin(trademark)xe2x80x9d) is used mainly to treat acute leukemia, rhabdomyosarcoma, neuroblastoma, Hodgkin""s disease and other lymphomas. The typical dose in 1.4 milligrams per square meter of body surface once a week, and neurotoxicity is the dose-limiting factor (it can cause damage to the peripheral nervous system). Because of this, people with neuromuscular disorders should steer clear of this drug if possible. Likewise, people with some forms of Charcot-Marie-Tooth syndrome should avoid vincristine. Pregnant women should definitely not take it, because it causes severe birth defects in animal tests. Other side effects include those found with vinblastine, plus additional nervous system problems such as sensory impairment; some people may also develop breathing problems or lung spasms shortly after the drug is administered. People occasionally can develop secondary cancers if they receive the drug along with other anticancer drugs that are known to be carcinogens.
Vindesine (xe2x80x9cEldisine(trademark)xe2x80x9d or xe2x80x9cFildesin(trademark)xe2x80x9d) is used mainly to treat melanoma and lung cancers and, with other drugs, to treat uterine cancers. It is administered at a dose of 3 milligrams per square meter of body surface. Its toxicity and side effects are similar to those of vinblastine.
Vinorelbine (xe2x80x9cNavelbine(trademark)xe2x80x9d) is indicated for the first-line treatment of non-small cell lung cancer (xe2x80x9cNSCLCxe2x80x9d)., sometimes in conjunction with cisplatin. The dosage is commonly 30 mg/m2. The side effects of this drug include diarrhea, nausea, hair loss and myelosuppression. Vinorelbine has been demonstrated to afford a longer survival time than vindesine, but it is a matter of two-four months better. A further improvement would be greatly welcome since there are so few therapeutic alternatives for patients with NSCLC cancer.
This invention also relates to methods for causing the use of an anti-neoplastic cGMP-phosphodiesterase inhibitor in combination with a vinca alkaloid derivative to be used for the treatment and prevention of pre-cancerous and cancerous lesions in mammals.
When a novel mechanism of action is announced to the world, competitors, even those with compounds that may act against secondary targets (e.g., sulindac which hits COX targets), can gain at the expense of the developer from suggesting to the medical community that their compounds act wholly or partially through the same novel mechanism. The advantages of such activities to such competitors is manifestly apparent to those skilled in the art of managing the business of pharmaceutical development.
This invention relates to an improved method of neoplasia therapy that involves treating a patient with both a vinca alkaloid derivative and a cyclic GMP-specific phosphodiesterase (PDE) inhibitor. The specific PDE inhibitors useful for this invention are compounds that inhibit both PDE5 and the types of PDE2 described below. The novel form of PDE2 disclosed herein is fully described by Liu, et al., in the copending U.S. Pat. No. 6,200,771, A Novel Cyclic GMP-Specific Phosphodiesterase And Methods For Using Same In Pharmaceutical Screening For Identifying Compounds For Inhibition Of Neoplastic Lesions. (For general PDE background, see, Beavo, J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms.
Physiological Reviews 75:725-747; web site  less than http://weber.u.washington.edu/xcx9cpde/pde.html greater than  (November 1998)).
In this invention, the cGMP-specific PDE inhibitor can be used in combination with a vinca alkaloid derivative in two ways. The first is a lower dosage methodology in which the traditionally recommended dose range of the vinca alkaloid derivative is decreased while its therapeutic effects are maintained and its side effects are attenuated. The second is a higher dosage methodology that utilizes the traditionally recommended dose range for the vinca alkaloid derivative and improves its activity without increasing its side effects. With each methodology, the vinca alkaloid derivative is administered simultaneously with or in succession with an appropriate cGMP-specific PDE inhibitor.
This invention also relates to packaged pharmaceutical compositions that are provided together with written materials describing the use of a cGMP-specific PDE inhibitor in combination with a vinca alkaloid derivative for the treatment of cancer and precancerous lesions.